An alarming increase in the prevalence of childhood asthma has been observed in the past several decades and is likely the result of an interaction among poorly understood immune, environmental, and genetic factors. Exercise is a common cause of asthma exacerbation in children, and it is now known that when children exercise, even healthy children engaged in real-life activities, a robust stress/inflammatory response ensues leading to activation of immune cells and cytokines, many of which are known to be involved in the pathogenesis of asthma. A seemingly paradoxical response to exercise occurs characterized by simultaneous and vigorous pro- and anti-inflammatory activation. Whether or not the naturally occurring leukocyte stress/inflammatory response to exercise is imbalanced in pediatric asthma and contributes to exercise-induced bronchoconstriction (EIB) has not been investigated in children. The goal of this Project is to test a series of hypotheses focused on novel mechanisms that link exercise with asthma pathogenesis in children. Specifically, the aims are: To systematically measure in children and adolescents with mild persistent asthma the effects of brief bouts of exercise on leukocyte production of key cytokines and growth factors that determine TH1, TH2, and T-regulatory balance. To measure the relationship between the leukocyte response to exercise and the magnitude of EIB in children and adolescents with asthma. To determine in children and adolescents with asthma how the acute leukocyte responses to exercise are altered by fitness, habitual physical activity, body composition, and gender and maturational status. The research relies on state-of-the-art techniques to assess gene regulation in leukocytes including: microarray, RT-PCR, flow cytometry for surface and intracellular expression of key cytokines, and growth factors. A series of in-vitro cell culture experiments have been designed to determine whether leukocytes in children with asthma differ in their responses to exercise than in healthy controls;or, alternatively, whether the mechanism is found in factors within the circulation (e.g., mediators such as growth hormone, insulin-like growth factor-l and its binding proteins, interleukin-6, and heat shock proteins- mediators that are altered by exercise and are known to influence stress and immune responses. Exercise will consist of cycle ergometry with gas exchange measured breath by breath. Habitual physical activity will be measured with accelerometry, and body composition with DEXA. Lung function will be measured by spirometry before and after exercise. Lay Summary. Asthma is the major chronic disease of childhood, and exercise and play are, unfortunately, key triggers of asthma attacks. This research is designed to better understand how immune cells respond to exercise in asthma. This knowledge will help develop strategies to limit asthma attacks permitting affected children to prevent chronic lung disease and fully accrue the many health benefits of exercise during growth.